MD2B - Acute Leukemias

Introduction

Leukemia is defined as a malignant, marrow-based neoplasm of hematopoietic or lymphoid cells. The key feature of leukemia is the presence of tumor cells circulating in the blood. Acute leukemia involves aberrant differentiation and proliferation of malignantly transformed progenitor cells, and can be rapidly fatal if untreated. The two main types of acute leukemia are named for the stem cell of origin: acute lymphoblastic leukemia (ALL )if it involves lymphocytes, and acute myeloid leukemia (AML) if it involves myelocytes. Of note, both lymphocytes and myelocytes are subtypes of white blood cells. While ALL and AML are clinically similar in that they both typically present with symptoms secondary to cytopenias (lowered cell counts), there are significant laboratory features and prognostic factors that can be used to distinguish ALL from AML and to dictate therapy, as discussed below.

Differences between ALL and AML [1]

• Clinical differences in early complications

• Morphologic differences

• Cytochemical differences

• Immunophenotypic differences
• • Lymphoid stem cells are TdT+
  • Other markers help distinguish B-cell ALL from T-cell ALL
  • Some ALL blasts also express myeloid antigens, but the presence of these antigens has no prognostic effect [2].

Acute Lymphoblastic Leukemia

• Classification
• • French-American-British (FAB) Morphologic Classification [1]

• Classification by Immunophenotype (World Health Organization recommended [3])

• Epidemiology, Etiology, and Pathogenesis
• • Most common malignancy in children; accounts for 80% of acute leukemia in children and 20% of acute leukemia in adults.
  • Incidence of ALL in children is 2300 new cases per year in the US, with a peak incidence seen between ages 2 - 5 [4]
  • Incidence is 20% higher in boys than girls, 100% higher in whites than blacks (Gurney children)
  • 5 year survival for ALL in children is 87% [5]
  • Etiology is possibly viral, but not well established.
  • Hereditary link is likely, as siblings of leukemia patients typically show a threefold higher risk of developing disease.
  • Increased risk is associated with Down's syndrome (15 X) and atomic bomb survivors (linear dose-response relationship) [6].
• Clinical Presentation
• • History: Generally cytopenia-related symptoms, such as fatigue, dyspnea, infections, bruising, weight loss, as well as bone pain
  • Physical Exam: Pallor, petechiae, signs of organ/tissue infiltration, fever, lymphadenopathy
  • Labs: Cytopenias (white blood cells, red blood cells and/or platelets)
  • Diagnostic Studies: peripheral smear, bone marrow biopsy, cytogenetic abnormalities
  • Note: The characteristic presentation of T cell ALL is an older age boy with mediastinal mass and leukocytosis.
• Natural Course
• • Staging is not clearly defined for ALL, and patients with confirmed diagnoses are grouped as:
  • 1. untreated (not in remission) - defined as an abnormal white blood cell count and differential, abnormal hematocrit/hemoglobin and platelet counts, abnormal bone marrow with more than 5% blasts, and signs and symptoms of the disease.
    2. in remission - where a patient has received remission-induction treatment and now has normocellular bone marrow with less than 5% blasts, no signs or symptoms of the disease, no signs or symptoms of central nervous system leukemia or other extramedullary infiltration, and all normal hematologic laboratory values.
    3. recurrence – defined as any failure since starting treatment, further characterized according to time since diagnosis and relapse site (bone marrow, extramedullary)
  • Prognosis – grouped into low-, standard-, and high-risk; grouping schemes (particularly genetic analysis) are an area of active research [7] Worse prognoses if:

• • age is <2 y or >9 y
  • male gender
  • high WBC counts
  • T-cell phenotype
  • low ploidy
  • presence of (4;11) or (9;22) chromosomal translocations [8].
  • presence of CNS disease
  • poor early response to treatment
• Treatment [7]
• • Risk assessment is critical to achieving cure with an acceptable degree of toxicity. Generally, patients with higher-risk disease receive more aggressive therapy.
  • High-dose chemotherapy regimens with at least two rounds of induction (prednisone or dexamethasone, vincristine, L-asparaginase, +/- an anthracycline), consolidation and maintenance.
  • • Long-term, disease-free survival is seen in 30-40% of patients [7]
  • Delayed intensification was a major advance in 1983, followed by advances in bone marrow transplantation (high dose chemo +/- total body irradiation followed by marrow infusion) [9]. Allogenic transplantation is of particular benefit in high-risk disease (chromosomal translocations) and after poor response to initial therapy.
  • Central nervous system coverage to prevent or treat disease (intrathecal chemotherapy or irradiation) is critical for long term control

Acute Myeloid Leukemia

• Classification
• • FAB Morphologic Classification

M0 - AML undifferentiated

M1 - AML without maturation

M2 - AML with maturation

M3 - Acute promyelocytic leukemia (APL)

M4 - Acute myelomonocytic leukemia (AMML)

M4eo -AMML with abnormal eosinophils

M5 - Acute monoblastic leukemia

M6 - Acute erythroleukemia

M7 - Acute megakaryoblastic leukemia

• WHO Classification (preferred for prognostic significance [10])

AML with recurrent genetic abnormalities

t(8;21) FAB M2, inv(16)/t(16;16), t(15;17) FAB M3, 11q23

AML with multilineage dysplasia (MPD)

following MDS/MPD, dysplasia in 2 or more cell lines

AML and myleodysplastic syndromes (MDS), therapy related

alkylating agents/radiation-related, topoisomerase II inhibitor-related

AML, not otherwise categorized

with subtypes identical to FAB classification

• Epidemiology, Etiology and Pathogenesis
• • Incidence of AML is 13,000 cases per year in the US [11]. AML accounts for 80-90% of adult acute leukemias, 10% of childhood leukemias and virtually all neonatal acute leukemias.
  • Etiologic factors are thought to include exposure to carcinogens and mutagens, such as benzene, alkylating agents and ionizing radiation; inherited genetic conditions such as Fanconi's anemia and Down's syndrome; and viruses.
  • Pathogenesis involves clonal evolution through multiple steps. AML etiology and pathogenesis is considered similar to myelodysplasia, (also known as MDS, refractory anemia, preleukemia or smoldering leukemia), which is a clonal abnormality of pluripotential stem cells with defective maturation and ineffective hematopoiesis

• Clinical Presentation
• • History: Present with cytopenia-related symptoms, as with ALL
  • Physical Exam: Pallor, petechiae, fever, organ involvement
  • Labs: Cytopenias common; consider a medical emergency if WBC count is >100,000 or there are DIC-type indices
  • Diagnostic Studies: Peripheral smear, bone marrow biopsy
• Natural Course
• • Staging is similar to ALL in that there is no clear-cut system; patients are classified as
  • 1. untreated - newly diagnosed leukemia with no prior treatment, abnormal bone marrow with more than 20% blasts, signs and symptoms of the disease, and typically abnormal hematologic cell counts
    2. in remission - a normal peripheral blood cell count and normocellular marrow with less than 5% blasts in the marrow, no signs or symptoms of the disease, and no signs or symptoms of central nervous system leukemia or other extramedullary infiltration.
    3. relapsed or refractory- evidence of disease as described above after achieving remission or unsuccessful treatment
  • Prognosis - three most important factors are age, WBC count, and cytogenetics [12]
    Unfavorable prognoses [6,12,13] for patients with:
    • age >60 y
    • WBC > 30,000
    • CNS involvement
    • disease secondary to MDS, chemo or XRT
    • CD34 +
    • MDR 1-positive
    • Complex karyotypic abnormalities
    Favorable prognosis with [12]:
    • t (8;21), inv(16)/t(16;16), t(15;17)

• Treatment
• • AML chemotherapy is administered in two basic phases, induction and post-remission.
  • Induction with daunorubicin + anthracycline with 70-80% complete remission rate, but also 100% relapse rate if no further therapy is given [14].
  • Post-remission therapy consists of consolidation chemo, giving 40-50% cure rates, or autologous and allogeneic bone marrow transplants, giving improved cure rates of 45-65% [15]
  • For APL t(15;17), whose unique fusion product PML-RARα contains retinoic acid receptor, regimens containing all-trans-retinoic acid (ATRA) as a differentiation agent results in remission rates around 90% and a 70% cure rate [16]
  • A retrospective analysis of long-term AML survivors showed a 13% incidence of malignancies secondary to treatment [17]